Molecular modeling study of structural requirements for the oligopeptide transporter.

The intestinal oligopeptide transporter (OPT) mediates the absorption of di-/tripeptides, beta-lactam antibiotics, angiotensin converting enzyme (ACE) inhibitors and renin inhibitors. This suggests that the targeting of molecules to this transporter could result in orally-absorbed drugs. Results from a recent study with renal brush border membrane vesicles (BBMV) suggested that an alpha-NH2 group is required for interaction with the renal OPT. In general, structural requirements for interaction with the renal and intestinal OPT are similar. However, these recent findings do not agree with earlier studies, which showed that an alpha-NH2 group is not essential for interaction with the intestinal OPT. Thus, it appears that the renal and intestinal OPT may differ in their recognition of compounds containing an alpha-NH2 group. In this study, molecular modeling was used to determine the tridimensional structures of various cephalosporins for which Ki values had been determined using renal BBMV. All cephalosporins which interact with the OPT have two, energetically equivalent, conformations. Most compounds which do not interact with the OPT cannot adopt the two conformations. A key factor which influences the conformation seems to be the substituent group at the alpha position; an electron drawing group at that position alters the common conformations. For the OPT substrates, the distances between the -NH2 and -COOH groups are comparable to those of the tripeptide, GlyGlyGly; and the distances between -NH2 and carbonyl group in the beta-lactam ring are close to the distance between N-terminal and C-terminal in the dipeptide, GlyGly. The corresponding distances in cephamycin C (in which a -NH2 group is located in a different position) and the tetrapeptide, GlyGlyGlyGly, are longer than those in alpha-NH2 cephalosporins and GlyGlyGly. Cephamycin C and the tetrapeptide have low affinity for the renal OPT, suggesting that the distances between functional groups are critical for affinity. The alpha-NH2 group had no effect on the conformations of the molecules. We concluded that the alpha-NH2 group may interact directly with the renal oligopeptide transporter. Whether this is unique to the renal transporter or could be applied to the intestinal transporter will require further investigation.